The present invention relates to the permanent augmentation of soft tissues and, more particularly to the treatment of urological disorders, e.g., urinary incontinence, and vesico-ureteral reflux, by endoscopic injection of biocompatible anionic microparticles into submucosal tissues.
Since this invention is closely related to the treatment of incontinence, it will be described in detail by reference thereto.
For a simple explanation, incontinence occurs when the resistance to urine flow has decreased excessively, i.e., urethral resistance to urine outflow has, from whatever cause, been lowered to the point when it can no longer resist increased intra-abdominal pressure.
Urinary incontinence is a usual problem that affects people of different ages. This pathology predisposes a patient to urinary tract infections and urosepsis among others.
Urinary incontinence is also associated with social and psychological problems, as people affected with urinary incontinence show depression and social stigmatization.
One of the treatments actually proposed to solve urinary incontinence is the injection of biocompatible polymeric materials in the internal tissue e.g., in the urethra, in order to augment the soft tissue and restore continence.
Many of the biocompatible materials that have been used for augmenting the soft tissues e.g. are collagen, gelatin, and especially one of the most biocompatible molecules: hyaluronic acid. Beads of these natural crosslinked polymers are also currently used. However, all of those polymers were also biodegradable.
More recently, the biomaterials used in the treatment of urinary incontinence are synthetic non-biodegradable polymers and hydrogel polymers such as silicone rubber, polytetrafluoroethylene, polyacrylonitrile-polyacrylamide, and polyacrilates. Moreover, those hydrogel polymers were loaded with biological biodegradable polymers or autologous cells.
Most often, the biomaterials and their biocompatible carriers are delivered to the tissue by injection with an appropriate syringe.
The use of various injectable polymeric materials to treat urinary incontinence through the augmentation of tissues is known in the art.
Related to the use of biocompatible, biodegradable polymers for tissue augmentation, U.S. Pat. No. 5,143,724 describes the use of viscoelastic polymers with high biocompatibility like hyaluronic acid or crosslinked hyaluronans. Those highly anionic materials show very low cell interaction, they are often used in cosmetic surgery, but they have limited use in tissue augmentation due to the fact that hyaluronic acid will spread out of the tissues and also because hyaluronic acid is degraded.
Another biocompatible biodegradable biopolymer used in the treatment of urinary incontinence is collagen protein. U.S. Pat. No. 4,837,285 to Berg et al., relates to a collagen-based composition for augmenting soft tissue. The inventors describe the use of resorbable matrix beads of collagen with an average pore size of about 50 to 350 μm. Berman C. J. et al., Journal of Urology. 1997, 157; 122-124), describe the use of crosslinked collagen in the treatment of urinary incontinence following radical prostatectomy. However, the use of collagen shows contradictory results. A study of McCell. M, and Delustro, F., published in 1996 in Journal of Urology 155, 2068-2973 suggests the possible sensitization in patients because specific IgG and IgA antibodies appear after injection of bovine collagen.
Non-biodegradable polymers were used, e.g., injection of polytetrafluoroethylene (PTFE) in the past was used to treat urinary incontinence, see Kaufman et al., “Transurethral polytetrafluoroethylene injection for post-prostatectomy Urinary incontinence” 1984—Journal of Urology .132, p 463-464.
However, the presence of very small PTFE particles in the formulations was a problem since undesirable particle migration and serious granulomatous reaction take place. One commercial product containing PTFE particles with a diameter lower than 30 μm suspended in glycerin is available under name Polytef® (trademark of Mentor Corp. of California).
In order to overcome the problem of the migration, it has been proposed to use polymer particles of larger size.
In U.S. Pat. No. 5,336,263, the use of microparticles of silicone (polysiloxane and dimethylsiloxanes), with an average particle size in the range of from about 100 to 600 μm, is described as a method for long-term treatment of urinary incontinence.
EP Patent application No. 636014, U.S. Pat No. 5,258,028, and U.S. Pat No. 5,336,263 describe the use of textured microparticles of silicone in the manufacture of a composition for the long term treatment of urological disorders, such as incontinence. The aforementioned microparticles are dispersed in a physiologically biocompatible carrier and have an average size between 80 and 600 μm. The composition can be injected through a hypodermic needle.
French Patent number 2 836 921 A1 also describes tissue bulking made of silicone. The inventors describe injectable foam particles with biocompatible characteristics that are suspended in a biocompatible carrier, in which most of said particles have a diameter between 100 and 2000 μm. The silicone foam particles used to treat urinary incontinence have a reversible compression capacity between 300 and 420%.
The other compositions mentioned in the treatment of urinary incontinence are described as non-biodegradable water insoluble polymers denominated hydrogel.
EP 402,031 relates to an injectable composition, comprising a plurality of polymeric discrete particles, physiologically compatible, non-biodegradable, and of an average diameter ranging between 0.27 and 5.08 mm, and having a lubricated surface. These microparticles are deformable in a reversible manner, in approximately 20 to 75% of their external diameter. This composition contains microparticles of polyacrylonitrile in regular shape: in the form of spheres or macrodiscs.
U.S. Pat No. 6,335,028 “Implantable particles for urinary incontinence” describes an injectable composition for the treatment of urinary incontinence, gastroesophageal reflux disease and amelioration of skin wrinkles, using a biocompatible hydrophilic cationic copolymer composed by acrylic monomer and cationic monomer. The spherical particles can be loaded with different therapeutic agents such as antidiuretic, anti-inflammatories, cell adhesion promoter etc., and also with autologous cells. The spherical microparticles have a diameter ranging between 10 to 1000 microns.
U.S. Published Patent Application 2002/0068089 describes a method for treating gastroesophageal reflux disease by injection of a bulking agent. This composition also contains cationic biocompatible hydrophilic microparticles that can be loaded with different therapeutic agents, including autologous cells. Those cationic particles have a diameter ranging between 10 to 1000 microns.
WO 0170289 “Injectable and swellable microspheres for tissue bulking” relates to injectable compositions comprising substantially spherical microspheres used for tissue bulking in the treatment of urinary incontinence, urinary reflux disease and gastro-esophageal reflux disease. The microspheres are hydrophilic, biocompatible, swellable polymers like acrylic polymers, starch-acrylonitrile polymers and also polyethylene oxide among others. This composition comprising microspheres also comprises an amount of 10 to 90% of biocompatible saline carrier that contain acylamino-e-propion-amido-3-triiodo-2,4,6-benzoic acid (a contrast agent) and the microspheres have the property to swell about 1 to 4 times their average diameter after injection in the tissues. The microspheres may also be chemically modified with different biological molecules with therapeutic properties. These microspheres may be associated with autologous cells.
From this state of the art, it appears that in recent years, many approaches and treatments have been proposed to cure or relieve urinary incontinence by injection. While some of these approaches have enjoyed relative success, relief has been, for the most part, only temporary in those patients where success is noted. Thus, there remains a very important need for a treatment that will provide a lasting remedy for successful treatment of such urological disorders.